Subgroup Efficacy Analyses of - PowerPoint Presentation

1. Subgroup Efficacy Analyses of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People With HIV in the Phase 2/3 CAPELLA Study1ICH Study Center Hamburg, Germany; 2Orlando Immunology Center, Orlando, Florida, USA; 3New York Presbyterian Queens, Flushing, New York, USA; 4I.R.C.C.S. Ospedale San Raffaele, Milano, Italy; 5Thai Red Cross AIDS Research Centre, Bangkok, Thailand; 6Hospital Clínic de Barcelona, Spain; 7Università Degli Studi di Brescia, Italy; 8Istituto Nazionale per le Malattie Infettive "L. Spallanzani," Roma, Italy; 9Hôpital Bichat–Claude-Bernard, France; 10Hôpital Sainte Marguerite, Marseille, France; 11Gilead Sciences, Inc., Foster City, California, USA; 12Hôpital Saint-Louis, ParisHans-Jürgen Stellbrink,1 Edwin DeJesus,2 Sorana Segal-Maurer,3 Antonella Castagna,4 Anchalee Avihingsanon,5 José Luis Blanco Arévalo,6 Francesco Castelli,7 Andrea Antinori,8 Yazdan Yazdanpanah,9 Sylvie Ronot-Bregigeon,10 Hui Wang,11 Nicolas Margot,11 Hadas Dvory-Sobol,11 Martin Rhee,11 Jared M. Baeten,11 Jean-Michel Molina1218th European AIDS Conference, October 27–30, 2021, London, UK: PE2/69

2. Introduction: Lenacapavir (LEN, GS-6207) Targets Multiple Stages of HIV Replication Cycle1,2EC50, half-maximal effective concentration; Gag, group antigens; Pol, polyprotein.2

3. 3LEN is a novel, highly potent, long-acting, first-in-class, HIV-1 capsid inhibitorLEN can meet significant unmet medical needs: A new mechanism of action for multidrug-resistant HIV-1Reduction of daily pill burden through less frequent dosing for treatment and preventionHighly desirable in vitro profile with picomolar antiviral activity (EC50: 50–100 pM) Retains full activity against nucleoside reverse-transcriptase inhibitor (NRTI)–, non-NRTI–, integrase strand transfer inhibitor (INSTI)–, and protease inhibitor (PI)–resistant mutants3-5No observed preexisting resistance3,6Subcutaneous (SC) LEN can be administered q6mo7LEN demonstrated potent antiviral activity in people with HIV (PWH), with up to 2.3 log decline8In treatment-naïve PWH, LEN + emtricitabine/tenofovir alafenamide led to 94% virologic suppression at Week 289In heavily treatment-experienced (HTE) people with multidrug resistant HIV-1:LEN achieved its primary endpoint as a functional monotherapy when added to a failing regimen10: Participants with ≥0.5-log decline: LEN 88% vs placebo 17% (p<0.001)HIV-1 RNA decline, mean: LEN 1.9 vs 0.3 log (p<0.001)LEN + optimized background regimen (OBR) led to 81% virologic suppression at Week 2611Introduction

4. ObjectiveTo evaluate Week 26 efficacy (assessed using U.S. Food & Drug Administration [FDA] Snapshot algorithm) by subgroup analyses in a randomized cohort by demographics and baseline HIV-1 RNA, cluster of differentiation-4 (CD4), INSTI resistance, and OBR4

5. n=24n=12SC LEN q6mo for 52 wk*OBR†OBR†Oral LEN*Failing regimenFailing regimenPlacebon=36Randomized cohort(double blind) Nonrandomized cohort (open label)SC LEN q6mo for 52 wk*Oral LEN*SC LEN q6mo for 52 wk*Oral LEN*OBR†OBR†Methods: Study DesignEfficacy was summarized only for the randomized cohort (n=36), as most in the nonrandomized cohort have not reached Week 26 yetSafety was summarized for both the randomized and nonrandomized cohorts (N=72)*Administered as 600 mg on Days 1 and 2, and 300 mg on Day 8; SC LEN administered as 927 mg (2 x 1.5 mL) in abdomen on Day 15; †Investigational agents, such as fostemsavir, were allowed; atazanavir (ATV), ATV/cobicistat, ATV/ritonavir, efavirenz, entecavir, ipranavir, and nevirapine were not allowed. ARV, antiretroviral.5Functional monotherapy (14 d)MaintenanceYESKey eligibility criteria:HIV-1 RNA ≥400 c/mLResistance to ≥2 agents from 3 of 4 main ARV classes≤2 fully active agents from 4 main ARV classesScreening PeriodPrerandomization repeat HIV-1 RNADecline ≥0.5 log c/mL(vs screening); or<400 c/mLNO

6. Results: Baseline Characteristics6RandomizedNonrandomizedLEN n=24Placebon=12LENn=36TotalN=72Age, median (range), years55 (24–71)54 (27–59)49 (23–78)52 (23–78)Sex, % female at birth29252225Race, % Black42553138Ethnicity, % Hispanic/Latinx25361421HIV-1 RNA, median (range), log10 c/mL4.2 (2.3–5.4)4.9 (4.3–5.3)4.5 (1.3–5.7)4.5 (1.3–5.7)>75,000 c/mL, %17502828CD4 count, median (range), cells/μL172 (16–827)85 (6–237)195 (3–1296)150 (3–1296)≤200 cells/μL, %67925364No. of prior ARV agents, median (range)9 (2–24)9 (3–22)13 (3–25)11 (2–25)No. of ARV agents in failing regimen, median (range)3 (1–7)3 (2–6)4 (2–7)3 (1–7)No. of ARV agents in OBR, median (range)4 (2–6)4 (2–7)4 (2–6)4 (2–7)No. of fully active agents in OBR, %017171717129583638≥2 54254746Known resistance to ≥2 drugs in class, %NRTI9610010099NNRTI9210010097PI83678381INSTI83586469

7. Composition of Failing Regimen and OBR17 of 72 participants (24%) had no changes in their OBRClass/Agent, %Failing Regimen: N=72OBR: N=72NRTI8285INSTI6865PI6363NNRTI3133Ibalizumab (CD4-directed postattachment inhibitor)1924Maraviroc (CCR5 entry inhibitor)1414Fostemsavir (attachment inhibitor)611Enfuvirtide (fusion inhibitor)67No. of fully active ARV agents, %0421713638≥22246OSS, median*1.02.07*Overall susceptibility scores (OSS; 1, 0.5, or 0 for full, partial, or no susceptibility, respectively) were determined based on proprietary algorithm (Monogram Biosciences Inc., South San Francisco, California, USA); for historical resistance reports, scores were derived from data provided by investigators; OSS of OBR was sum of individual scores. CCR5, C-C chemokine receptor type-5.

8. Efficacy at Week 26 in Randomized Cohort (n=36)FDA-Snapshot Algorithm118HIV-1 RNA, c/mLNo Virologic Data72932n=4<50≥50<200≥20000HIV-1 RNA, c/mLParticipants, %

9. Efficacy by Demographics**Prespecified subgroup analyses; †Total n in each subgroup; ‡1 participant with race reported as “not permitted.” CI, confidence interval.9Age, years<50Male≥50FemaleSex at BirthBlackNon-BlackRace‡OverallUSAEx-USARegion10077749081848183719262710161936297n=†

10. Efficacy by Baseline CD4 and HIV-1 RNA**Prespecified subgroup analyses; †Total n in each subgroup.10CD4, cells/μL<200≤100,000≥200>100,000HIV-1 RNA, c/mLOverall788689578127299736 n=†

11. Efficacy by No. of Fully Active Agents in OBR* 110≥2161614678186No. of Fully Active Agents in OBR*Post hoc subgroup analyses; †Total n in each subgroup.Overall8136 n=†

12. n=†Efficacy by Baseline OBR Sensitivity Score**Prespecified subgroup analyses; †Total n in each subgroup.12OSS92786712186Overall81360–<11–<2≥2

13. Efficacy by Baseline INSTI Resistance**Prespecified subgroup analyses; †Total n in each subgroup; ‡Included phenotypic and genotypic resistance to bictegravir, cabotegravir, dolutegravir (DTG), elvitegravir, and raltegravir; 1 participant had missing baseline INSTI resistance data.13INSTI Resistance‡YesNoOverall85638127836n=†

14. Efficacy by Baseline Use of Dolutegravir and/or Darunavir*14DTGYesYesNoNoDRVYesNoDTG or DRVOverall838178808178811821181527936n=†*Post hoc subgroup analyses; †Total n in each subgroup. DRV, darunavir.

15. 15DTG, no DRVDRV, no DTGOverallDTG and DRV83837881781269369n=†No DTG or DRVEfficacy by Baseline Use of Dolutegravir and/or Darunavir**Post hoc subgroup analyses; †Total n in each subgroup.

16. Efficacy by Baseline Use of Ibalizumab**Post hoc subgroup analyses; 3 participants were on fostemsavir and all had HIV-1 RNA <50 c/mL at Week 26; †Total n in each subgroup.16IMABYesNoOverall758381122436n=†

17. ConclusionsIn HTE PWH with limited treatment options due to multidrug resistance, LEN demonstrated a clinically meaningful contribution towards virologic suppression in combination with an OBRNo clinically relevant differences were seen in efficacy among subgroups who were considered more difficult to treat (eg, those with low CD4 count, INSTI resistance, no fully active agents, or no DTG or DRV in the OBR)LEN has the potential to become an important agent for HTE PWH with multidrug resistanceThese data support the ongoing evaluation of LEN for treatment and prevention of HIV17

18. References1. Bester SM, et al. Science 2020;370:360-4; 2. Link JO, et al. Nature 2020;584:614-8; 3. Margot N, et al. CROI 2020, poster 529; 4. VanderVeen L, et al. CROI 2021, oral 01781; 5. Yant SR, et al. CROI 2019, poster 480; 6. VanderVeen L, et al. IDWeek 2021, oral 73; 7. Begley R, et al. AIDS 2020, poster PEB0265; 8. Daar E, et al. CROI 2020, poster 3691; 9. Gupta SK, et al. IAS 2021, oral OALB0302; 10. Segal-Maurer S, et al. CROI 2021, oral 2228. 11. Molina JM, et al. IAS 2021, oral OALX01LB02.18

19. AcknowledgmentsWe extend our thanks to:The study participants and their familiesParticipating study investigators and staff: Canada: J Brunetta, B Trottier; Dominican Republic: E Koenig; France: J-M Molina, S Ronot-Bregigeon, Y Yazdanpanah; Germany: H-J Stellbrink; Italy: A Antinori, A Castagna, F Castelli; Japan: T Shirasaka, Y Yokomaku; South Africa: M Rassool; Spain: J Mallolas; Taiwan: C-C Hung; Thailand: A Avihingsanon, P Chetchotisakd, W Ratanasuwan, K Siripassorn; United States: DS Berger, M Berhe, C Brinson, CM Creticos, GE Crofoot, E DeJesus, D Hagins, T Hodge, K Lichtenstein, JP McGowan, O Ogbuagu, O Osiyemi, GJ Richmond, MN Ramgopal, PJ Ruane, W Sanchez, S Segal-Maurer, J Sims, GI Sinclair, DA Wheeler, A Wiznia, K Workowski, C ZurawskiThis study was funded by Gilead Sciences, Inc.19